Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• Research (HZI), Inhoffenstraße 7, D-38124 Braunschweig, Germany 10.3762/bjoc.10.49 Abstract The preparation of alkyne-modified ansamitocins by mutasynthetic supplementation of Actinosynnema pretiosum mutants with alkyne-substituted aminobenzoic acids is described. This modification paved the way to

• introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3. Keywords: ansamitocins; antibiotics

• , we demonstrated that the ansamitocins (maytansinoids) 3–5 are an ideal showcase for creating small libraries by mutasynthesis [8][9][10]. These secondary metabolites exert strong antiproliferative activity towards different leukemia cell lines as well as human solid tumors. Inhibitory concentrations

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• . Keywords: ansamitocins; antibiotics; antitumor agents; mutasynthesis; natural products; Introduction Natural products still play an important role as lead structures for the treatment of infectious diseases and cancer. However, natural products have lost some of their attraction for the development of

• further modification of an advanced biosynthetic intermediate with an established core structure towards bioactive natural products and analogues is conducted, mutasynthesis may be regarded as the “endgame” of a total synthesis [4]. The ansamitocins (maytansinoids) 3–5 are ideally suited for mutasynthetic

• modifications and the creation of new analogues because they are highly potent antitumor active compounds that inhibit the growth of different leukemia cell lines as well as human solid tumors at very low concentrations (10−3 to 10−7 µg/mL) [8]. In contrast to colchicine, maytansinoids such as ansamitocins bind